Staphylococcus aureus is a major threat to global health as it is highly virulent and can infect virtually any organ in the body. Staphylococcal infections occur in both hospital settings and in the community, and concern over the spread of these infections is compounded by the fact that strains of S. aureus have become resistant to all commonly-used antimicrobials. Identifying host and bacterial factors that promote invasive disease is critical to our ability to prevent and treat staphylococcal infections. Vertebrates have developed several mechanisms to combat infection, including the sequestration of nutrients that are critical to microbial growth, termed nutritional immunity. Iron is one such essential nutrient that is required for S. aureus growth, but is often sequestered inside the host by iron-binding proteins, the most abundant of which is hemoglobin. Hemoglobin sequences vary among vertebrates as well as within the human population. The structure of human hemoglobin differs during gestational and post-birth development, and polymorphisms within the globin genes expressed in adult life are some of the most common hereditary mutations in humans. To combat host- mediated iron sequestration, S. aureus has evolved specific iron acquisition systems that bind host hemoglobin and remove the iron-containing heme for use as a nutrient source. Recent studies have demonstrated that S. aureus preferentially recognizes human hemoglobin over hemoglobin from other animal species and this species-specific recognition is due to differences in the surface-exposed portion of the hemoglobin molecule. In preliminary results reported in this application, we reveal that naturally occurring polymorphisms within human hemoglobin impact capture by S. aureus, suggesting that the structure of hemoglobin affects the ability of S. aureus to efficiently use it as an iron source. Moreover, we have found that S. aureus more efficiently bind the adult form of hemoglobin as compared to structurally distinct fetal hemoglobin. These data suggest that neonates may exhibit resistance to systemic staphylococcal infections and are consistent with clinical reports that the majority of S. aureus infections in children are non-invasive. Based on these fundamental observations, we hypothesize that the structure of human hemoglobin influences recognition by S. aureus and that this altered recognition impacts bacterial iron acquisition and S. aureus infection in vivo. T address this hypothesis we propose three Specific Aims: Aim 1: Define the mechanism by which S. aureus preferentially recognizes adult hemoglobin over fetal hemoglobin. Aim 2: Determine the impact of fetal hemoglobin on the host-pathogen interaction using an in vivo model of systemic S. aureus infection. Aim 3: Identify human hemoglobin polymorphisms that impact susceptibility to S. aureus infection. These studies will begin to elucidate the contribution of feal hemoglobin to bacteria-host interactions. Moreover, this work will provide critical insight into human genetic factors that increase susceptibility to severe staphylococcal infection, thereby permitting rational prophylaxis and improved outcomes for at-risk patient populations. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is one of the leading causes of bacterial infection in the United States, and this threat to public health has been magnified by the emergence of antibiotic-resistant strains. Our proposed studies will provide mechanistic insights into how S. aureus utilizes human hemoglobin as a nutrient iron source during infection, and will examine the impact of human hemoglobin polymorphisms on susceptibility to S. aureus disease. Results obtained from these studies may lead to the development of a personalized medicine-based approach to the prevention and treatment of systemic staphylococcal infections.